Interstitial cystitis (IC) is a chronic bladder disease, of unknown origin, characterized by symptoms of pain, such as pelvic pain, and lower urinary tract symptoms (LUTS) such as increased urinary frequency/urgency. More recently terminology has evolved to include painful bladder syndrome (PBS) (MacDiarmid S A et al. Rev Urol 2007; 9(1): 9-16) or bladder pain syndrome (BPS) (van der Merve et al. European Urology 53(2008) 60-67, along with IC, that is IC/PBS/BPS to collectively describe this symptom complex.
Prevalence rates of IC/PBS/BPS vary from 67 to 230 per 100,000 women having clinically confirmed disease, although the number is likely higher than this due to under- or mis-diagnosis, commonly as endometriosis, recurrent urinary tract infection, overactive bladder or vulvodynia (Forrest J B et al. Clinical Courier 2006; 24(3): 1-8). IC has a significant impact on quality of life, affecting travel, family relationships, and employment (Slade D et al. Urol 1997; 49 (5A Suppl): 10-3), as well as being associated with depressive symptoms (Rothrock N E et al. J Urol 2002; 167: 1763-1767).
There are few well performed, placebo-controlled, randomized trials of therapies aimed at IC, and treatment often consists of a multimodal trial-and-error approach, as evidenced by one review of patients in the Interstitial Cystitis Data Base study which reported 183 different types of treatment (Rovner E et al. J Urol 2000; 56: 940-5).
No single etiology has been identified, and it is most likely a multifactorial process with several urologic insults causing a self-perpetuating process of epithelial cell dysfunction, C-nerve fibre activation, and proliferation of mast cells, leading to worsening tissue damage, scarring and fibrosis. The repetitive stimulation of C fibres from inflammation, and upregulation of sensory nerves in the bladder, ultimately leads to permanent alterations (centralization) resulting in hyperalgesia, chronic bladder pain and voiding dysfunction (Forrest J B et al. Clinical Courier 2006; 24(3):1-8).
Although no consensus has been reached on the fundamental causes of IC, existing data have led to speculation that three pathophysiologic mechanisms may be implicated: epithelial dysfunction, mast cell activation, and neurogenic inflammation (Nazif O et al. Urol 2007; 69 (Suppl 4A): 24-33).
There is a continuing need to provide a novel, effective treatment for pain and/or a lower urinary tract symptom of interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome without the adverse effects or limited efficacy of currently available therapies.
There has been a report that a recombinant human anti-NGF (nerve growth factor) antibody has been tested in patients with interstitial cystitis (Dimitrakov, et al., J. Urology. Vol 171(4), Supplement, 363 (2004)). Although the objective of the study was to evaluate the efficacy and safety “in a group of IC patients with significant nerve damage and neuropathic pain component who have failed numerous previous treatments”, only effects on nerve damage were reported using urinary nerve damage marker levels. It is important to note that no efficacy is reported in treating pain and/or a lower urinary tract symptom of the condition.
The anti-NGF antibody E3 has previously been reported as being useful in the treatment of pain, including rheumatoid arthritis pain, osteoarthritis pain and post-surgical pain (see for example WO2004/058184). However, given the etiology of interstitial cystitis and poor mechanistic understanding of the condition, it cannot be easily predicted that an anti-NGF antibody, such as antibody E3, could be used for treating pain and/or a lower urinary tract symptom (LUTS) associated with interstitial cystitis and/or painful bladder syndrome and/or bladder pain syndrome.